1. Field of the Invention
The present invention relates to a method for quantifying drug delivery. More specifically, it relates to the method and the application for quantifying microbubble drug delivery using contrast-enhanced ultrasound.
2. Description of the Related Art
Ultrasound-Triggered Microbubble Destruction (UTMD) is a promising strategy to increase local drug concentration at pathologic site while reducing systemic toxicity wherein drug is loaded in micron-sized or nanometer-sized bubbles whose destruction is then triggered by ultrasound at the treatment site in order to deliver drug to the target. However, in clinical applications, other factors pose additional challenge. First, the ultrasound is attenuated to different degrees before they reach the target due to different tissue thickness and composition and tumor structure. Second, the concentration of micro-bubbles in the target area can vary depending on vascular factors such as tumor angiogenesis or tumor central necrosis. Third, if antibody-conjugated microbubbles are used, they will aggregate at specific sites so as to enhance the effect of ultrasound-triggered drug delivery. These factors will affect the actual amount of microbubble destroyed and influence the efficacy of drug delivery and a way to quantify ultrasound-triggered microbubble destruction will be useful to clinicians.
Several imaging modalities including magnetic resonance imaging (MRI), positron emission tomography (PET), single photon emission computed tomography (SPECT) and contrast-enhanced ultrasound (CEUS) have been used to monitor drug pharmacokinetics. However, all of these have their limitations. Despite the advantage of high tissue and spatial precision, none rigid pseudo signal and ionizing radiation of MRI, it doesn't allow to be used on individuals with implants such as pacemakers or defibrillators, the sensibility of partial contrast agent is inferior, and cannot provide fix-quantity drug delivery. On the other hand, the PET/SPECT requires radiolabelled microbubbles for depicting local drug concentration that risks the whole body of the subject under radiation.
Contrast-enhanced ultrasound imaging uses microbubbles loaded with filling gas. By means of the difference in echogenicity between the gas in the microbubbles and the soft tissue, it generates the reflected ultrasound and thus distinctive image with better contrast. While this method can assure the presence of microbubbles at the treatment site and is of the advantage of non-invasive, high resolution, instant scan, non-radioactive, low cost and user friendliness, the signal saturation of the image during the destruction of bubbles triggered by the ultrasound disqualifies the ultrasound as a quantifying tool. In recent studies, some scholars have attempted to quantify UTMD indirectly using a downstream method, by measuring the difference in echogenicity between and upstream location and a downstream location. However, in clinical operation, because the downstream vessel is a complex venous network that contains a mixture of sonicated and non-sonicated blood and the angiogenesis of tumors varies with different individuals. These make it difficult to measure vascular sonographic signal accurately, at or near the drug delivery zone.